Fluorine effects on structural, physical, biological, and agrochemical properties of organofluorine compounds

Abstract

Stereochemistry is an important area of organic chemistry since the molecular structure rules biological, physicochemical, and spectroscopic properties, besides the reactivity of organic compounds. The conformational isomerism, an aspect of conformational analysis and, therefore, of the stereochemistry field, is ruled by classical (steric and electrostatic) and nonclassical effects (electron delocalization). The knowledge of these factors allows for the conformational control of organic compounds to optimize reaction conditions, biological responses, and material properties. The fluorine atom has unique structural and induces well-known conformational effects, such as the gauche effect. Therefore, the fluorine introduction in a molecule is a pivotal strategy for conformational control, and the organofluorine is a chemical class with application in a variety of science fields. In this work, we exploited the impact on chemical, physical and biological characteristics at the molecular level caused by the introduction of fluorine atoms, both theoretically and experimentally, since this element can be used to improve key features in specific systems. This work is divided into two parts. 1st) Impact on stereoelectronic features and conformational control: a study of the gauche effect in 2-halofluoroethanes and 2-haloethanols, expanding to iodine compounds, since conformational effects involving iodine have not been explored in details. In addition, the fluorine atom can establish an electrostatic gauche effect with phosphorus, similar to that found in -fluoroethyl sulfonium motifs. For this reason, some β-fluoroethyl-phosphorus compounds were also studied. 2nd) Impact on biological properties: the replacement of chlorine with fluorine atoms in pesticide molecules with agricultural application was evaluated, since C−F bonds bring desirable features (more polar and, generally, stable bonds, with a lesser propensity to bioaccumulation). Also, inhalational fluorinated anesthetics were further studied to gain insight into the influence of stereoelectronic effects on the conformation and, subsequently, in the gas/blood partition coefficient of these compounds — it is known that the partition coefficient is an important parameter used to predict drug absorption through the body. Stereoelectronic features are directly related to the molecular dipolar moment, which is responsible for the permeation of the drugs throughout the cell membrane. Theoretical calculations based on the post Hartree-Fock method (MP2) and density functional theory (DFT) were performed. X-ray diffraction was also used. In the second part, the docking technique was carried out to predict energies and binding modes of ligand-protein interactions. It was observed that the fluorine atom modulates the conformational preferences of organic compounds. In addition, fluorine provides an electrostatic gauche effect when it is in a vicinal position to a partially charged phosphorus atom. Also in the second part, an important finding is that the bioisosteric replacement of chlorine with fluorine improves desirable features in compounds with an application, such as pesticides. This is due to the higher polarity and stability of the C−F bond compared to C−Cl, besides the decrease in lipophilicity, a parameter used as an indication of bioaccumulation in the body. Finally, we demonstrated the dependence of the partition coefficient and dipolar moment of the most stable conformers of volatile fluorinated anesthetics.